ULTOMIRIS (ravulizumab) (SHUa)

Key points

Favourable opinion for reimbursement in the treatment of patients with a body weight of 10 kg or above with atypical haemolytic uremic syndrome (aHUS) who are complement inhibitor treatment-naïve or have received eculizumab for at least 3 months and have evidence of response to eculizumab.

What therapeutic improvement?

No clinical added value in the therapeutic strategy including eculizumab (SOLIRIS).

Role in the care pathway?

The initial treatment of aHUS differs in adults and children:

• In adults: given the frequency of TTP in cases of TMA and the frequency of secondary HUS, treatment with plasma exchange is generally used as first-line therapy, while the diagnosis remains uncertain. In the event of a family history of aHUS or aetiological arguments in favour of aHUS, treatment with eculizumab may be used from the outset.
• In children: eculizumab is the first-line treatment given the rarity of differential diagnoses, apart from STEC-HUS. Plasma exchanges (PE) and plasma therapy in general, are not considered as first-line treatment due to the technical difficulties related to access approaches and the infectious risks. This type of treatment will only be proposed in the event of the unavailability of eculizumab or in the specific case of neonates.

In patients with anti-FH antibodies, various protocols may be proposed, which may include plasma exchanges, medicinal products without an MA in aHUS (cyclophosphamide, rituximab, mycophenolate mofetil), eculizumab and/or corticosteroid therapy.

Currently, in patients with end-stage kidney failure, liver-kidney transplantation is no longer recommended due to the morbidity and mortality associated with this method compared to the option of renal transplantation along with long-term eculizumab treatment, with a very good long-term prognosis.

In aHUS patients dialysed for less than 3 months, treatment with eculizumab will be initiated. It is necessary to continue eculizumab treatment for 3 to 6 months before concluding that there is no benefit. In the event of chronic dialysis, it is not appropriate to treat with eculizumab unless there is extra-renal injury associated with TMA.

Patients treated with eculizumab must be vaccinated against meningococcal infections before the start of treatment and take long-term prophylactic antibiotic therapy with full-dose phenoxymethylpenicillin as 2 doses per day (or macrolides in the event of allergy) from the start of treatment, and to be continued throughout treatment, and for 60 days following its discontinuation (until normalisation of CH50 in children).

The criteria for discontinuation of eculizumab treatment are not strictly defined in the guidelines or in the SPC. It is possible to stop treatment following the opinion of an expert centre, taking into account the type of genetic mutation found or otherwise, the outcome and the risk of recurrence. Discontinuation requires close laboratory monitoring to detect the reappearance of signs of haemolysis or organ involvement.

Infections are known trigger factors for aHUS episodes. In the absence of any immunotherapy, it is important to effectively vaccinate patients in accordance with the French vaccination schedule. Although vaccines can trigger an episode of TMA by stimulating the immune system, the risk in the event of known infection is higher.

Role of the medicinal product in the care pathway:

ULTOMIRIS (ravulizumab), the second complement C5 inhibitor, is a first-line therapy in the treatment of patients with a body weight of 10 kg or above with atypical haemolytic uremic syndrome (aHUS) who are complement inhibitor treatment-naïve or have received eculizumab (SOLIRIS) for at least 3 months and have evidence of response to eculizumab. However, in the absence of a direct comparison with eculizumab, the role of ravulizumab cannot be specified compared to this medicinal product. The Committee reiterates that ravulizumab (ULTOMIRIS) has no marketing authorisation in patients not having responded to eculizumab. ULTOMIRIS (ravulizumab) does not have an MA in children weighing less than 10 kg in contrast with eculizumab (SOLIRIS), which has an MA from 5 kg.

Insofar as ULTOMIRIS (ravulizumab) is a complement protein C5 inhibitor that increases the patient’s predisposition to meningococcal infection or septicaemia due to its mechanism of action, its prescription must be combined with vaccination against meningococcal infections using the ACYW conjugated tetravalent vaccine and the serogroup B invasive meningococcal infection vaccine, in accordance with 2020 vaccination schedule guidance. In addition, and in the same way as for SOLIRIS (eculizumab), another complement protein C5 inhibitor, the Committee recommends prophylactic antibiotic therapy for all patients treated with ULTOMIRIS (ravulizumab).